Mitochondria inside acute myeloid leukemia cells hydrolyze ATP to resist chemotherapy DOI Creative Commons
James T. Hagen, McLane M. Montgomery, Raphael Taiwo Aruleba

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: April 15, 2024

ABSTRACT Despite early optimism, therapeutics targeting oxidative phosphorylation (OxPhos) have faced clinical setbacks, stemming from their inability to distinguish healthy cancerous mitochondria. Herein, we describe an actionable bioenergetic mechanism unique mitochondria inside acute myeloid leukemia (AML) cells. Unlike cells which couple respiration the synthesis of ATP, AML were discovered support inner membrane polarization by consuming ATP. Because matrix ATP consumption allows survive stress, hypothesized that may resist cell death induced OxPhos damaging chemotherapy reversing synthase reaction. In this, targeted inhibition BCL-2 with venetoclax abolished flux without impacting mitochondrial potential. surviving cells, sustained was dependent on consumption. Mitochondrial further enhanced in made refractory venetoclax, consequential downregulations both proton-pumping respiratory complexes, as well endogenous F 1 -ATPase inhibitor ATP5IF1 . treatment-naive AML, knockdown sufficient drive resistance, while overexpression impaired activity and heightened sensitivity venetoclax. Collectively, our data identify a cancer-cell intrinsic vulnerability context chemotherapy.

Language: Английский

The HOX Gene Family’s Role as Prognostic and Diagnostic Biomarkers in Hematological and Solid Tumors DOI Open Access
Kaci Kopec,

Danielle Quaranto,

Nicole R. DeSouza

et al.

Cancers, Journal Year: 2025, Volume and Issue: 17(2), P. 262 - 262

Published: Jan. 15, 2025

The HOX gene family encodes for regulatory transcription factors that play a crucial role in embryogenesis and differentiation of adult cells. This highly conserved genes consists thirty-nine humans are located four clusters, A–D, on different chromosomes. While early studies the have been focused embryonic development its related disorders, research has shifted to examine aberrant expression subsequent implication cancer prediction progression. Due their encoding master factors, abnormal shown affect all stages tumorigenesis metastasis. review highlights novel family’s clinical relevance as both prognostic diagnostic biomarkers hematological solid tumors.

Language: Английский

Citations

0
STX1A regulates ferroptosis and chemoresistance in gastric cancer through mitochondrial function modulation DOI
Yan Niu, Chunyu Liu, Lizhou Jia

et al.

Human Cell, Journal Year: 2025, Volume and Issue: 38(3)

Published: March 8, 2025

Language: Английский

Citations

0
Acute myeloid leukemia mitochondria hydrolyze ATP to support oxidative metabolism and resist chemotherapy DOI
James T. Hagen, McLane M. Montgomery, Raphael Taiwo Aruleba

et al.

Science Advances, Journal Year: 2025, Volume and Issue: 11(15)

Published: April 9, 2025

OxPhos inhibitors have struggled to show a clinical benefit because of their inability distinguish healthy from cancerous mitochondria. Herein, we describe an actionable bioenergetic mechanism unique acute myeloid leukemia (AML) Unlike cells that couple respiration ATP synthesis, AML mitochondria support inner-membrane polarization by consuming ATP. Matrix consumption allows survive stress. Thus, hypothesized may resist chemotherapy-induced cell death reversing the synthase reaction. In support, BCL-2 inhibition with venetoclax abolished flux without affecting mitochondrial polarization. surviving cells, sustained depended on matrix consumption. Mitochondrial was further enhanced in made refractory venetoclax, consequential down-regulations endogenous F 1 -ATPase inhibitor ATP5IF1. Knockdown ATP5IF1 conferred resistance, while overexpression impaired activity and heightened sensitivity venetoclax. These data identify as cancer cell–intrinsic vulnerability context targeted chemotherapy.

Language: Английский

Citations

0
Mitochondria inside acute myeloid leukemia cells hydrolyze ATP to resist chemotherapy DOI Creative Commons
James T. Hagen, McLane M. Montgomery, Raphael Taiwo Aruleba

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: April 15, 2024

ABSTRACT Despite early optimism, therapeutics targeting oxidative phosphorylation (OxPhos) have faced clinical setbacks, stemming from their inability to distinguish healthy cancerous mitochondria. Herein, we describe an actionable bioenergetic mechanism unique mitochondria inside acute myeloid leukemia (AML) cells. Unlike cells which couple respiration the synthesis of ATP, AML were discovered support inner membrane polarization by consuming ATP. Because matrix ATP consumption allows survive stress, hypothesized that may resist cell death induced OxPhos damaging chemotherapy reversing synthase reaction. In this, targeted inhibition BCL-2 with venetoclax abolished flux without impacting mitochondrial potential. surviving cells, sustained was dependent on consumption. Mitochondrial further enhanced in made refractory venetoclax, consequential downregulations both proton-pumping respiratory complexes, as well endogenous F 1 -ATPase inhibitor ATP5IF1 . treatment-naive AML, knockdown sufficient drive resistance, while overexpression impaired activity and heightened sensitivity venetoclax. Collectively, our data identify a cancer-cell intrinsic vulnerability context chemotherapy.

Language: Английский

Citations

1